Synthesis and biological characterization of novel hybrid 7-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol and their heterocyclic bioisosteric analogues for dopa

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• 作者：Dutta ; Aloke K. ; Venkataraman ; Sylesh K. ; Fei ; Xiang-Shu ; Kolhatkar ; Rohit ; Zhang ; Shijun ; et. al.
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2004
• 出版时间：August 15, 2004
• 年：2004
• 卷：12
• 期：16
• 页码：4361-4373
• 全文大小：407 K

文摘

In a recent preliminary communication we described the development of a series of hybrid molecules for the dopamine D2 and D3 receptor subtypes. The design of these compounds was based on combining pharmacophoric elements of aminotetralin and piperazine molecular fragments derived from known dopamine receptor agonist and antagonist molecules. Molecules developed from this approach exhibited high affinity and selectivity for the D3 receptor as judged from preliminary [³H]spiperone binding data. In this report, we have expanded our previous finding by developing additional novel molecules and additionally evaluated functional activities of these novel molecules in the [³H]thymidine incorporation mitogenesis assay. The binding results indicated highest selectivity in the bioisosteric benzothiazole derivative N6-[2-(4-phenyl-piperazin-1-yl)-ethyl]-N6-propyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine (<b>14b>) for the D3 receptor whereas the racemic compound 7-({2-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-ethyl}-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-ol (<b>10cb>) showed the strongest potency. Mitogenesis studies to evaluate functional activity demonstrated potent agonist properties in these novel derivatives for both D2 and D3 receptors. In this regard, compound 7-{[4-(4-phenyl-piperazin-1-yl)-butyl]-prop-2-ynyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol (<b>7bb>) exhibited the most potent agonist activity at the D3 receptor, 10 times more potent than quinpirole and was also the most selective compound for the D3 receptor in this series. Racemic compound <b>10ab> was resolved; however, little separation of activity was found between the two enantiomers of <b>10ab>. The marginally more active enantiomer (−)-<b>10ab> was examined in vivo using the 6-OH-DA induced unilaterally lesioned rat model to evaluate its activity in producing contralateral rotations. The results demonstrated that in comparison to the reference compound apomorphine, (−)-<b>10ab> was quite potent in inducing contralateral rotations and exhibited longer duration of action.